Treatment for drug-resistant tuberculosis is largely delivered through standardised, empirical combination regimens in low-resource, high-burden settings. However, individualised treatment, guided by detailed drug susceptibility testing, probably results in improved individual outcomes and is the standard of care in well-resourced settings. Driven by the urgent need to scale up treatment provision, new tuberculosis drugs, incorporated into standardised regimens, are being tested. Although standardised regimens are expected to improve access to treatment in high-burden settings, they are also likely to contribute to the emergence of resistance, even with good clinical management.

2. A Cluster-Randomized Trial of Blood-Pressure Reduction in Black Barbershops

Non-Hispanic black men have the highest rate of hypertension-related death of any racial, ethnic, or sex group in the United States. Black men have less physician interaction than black women and lower rates of hypertension treatment and control, necessitating community outreach. Health outreach to…

Oral fluid tests for HIV are less sensitive than blood tests and more likely to miss recent infections, thanks to lower levels of viral antibodies in saliva compared with blood. Yet saliva tests, which are more practical and cheaper than blood tests, are commonly used to screen for HIV in public health settings where the use of needles may be unsafe or logistically difficult. These settings include jails, community-based organizations without certified phlebotomists on staff, and high schools and community colleges.

High mobility group box 1 (HMGB1) is a non-histone DNA-binding protein, secreted into the extracellular milieu in response to inflammatory stimuli. The secreted HMGB1 mediates various inflammatory diseases, including periodontitis; however, the underlying mechanisms of HMGB1-induced periodontal inflammation are not completely understood. Here, we examined whether anti-HMGB1 neutralizing antibody inhibits periodontal progression and investigated the molecular pathology of HMGB1 in vitro and in vivo. In vitro analysis indicated that HMGB1, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interleukin-1β (IL-1β) were secreted in response to tumor necrosis factor-α (TNF-α) stimuli in human gingival epithelial cells (HGECs) and human monocytic leukemia cells (THP-1) treated with phorbol myristate acetate. Increased levels of GM-CSF and IL-1β were observed in the conditioned media from TNF-α-stimulated HGECs and THP-1 in vitro. Simultaneous stimulation with TNF-α and anti-HMGB1 antibody significantly decreased TNF-α-induced inflammatory cytokine secretion. Experimental periodontitis was induced in mice using Porphyromonas gingivalis-soaked ligatures. The extracellular translocation was confirmed in gingival epithelia in the periodontitis model mice by immunofluorescence analysis. Systemic administration of anti-HMGB1 neutralizing antibody significantly inhibited translocation of HMGB1. The anti-HMGB1 antibody inhibited periodontal inflammation, expression of IL-1β and C-X-C motif chemokine ligand 1 (CXCL1), migration of neutrophils and bone resorption, shown by bioluminescence imaging of myeloperoxidase activity, quantitative RT-PCR and micro-computed tomography analysis. These findings indicate that HMGB1 is secreted in response to inflammatory stimuli caused by periodontal infection, which is crucial for the initiation of periodontitis, and anti-HMGB1 antibody attenuates the secretion of a series of inflammatory cytokines, consequently, suppressing the progression of periodontitis.

5. Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout

Gout is a chronic illness characterized by hyperuricemia, arthropathy, tophus development, and urolithiasis and is associated with an increased risk of cardiovascular and chronic kidney disease. The risk of cardiovascular events, including death, is substantially higher in people with gout than in…

Helicobacter pylori, a Gram-negative bacterium, is a well-known risk factor for gastric cancer. H. pylori vacuolating cytotoxin A (VacA) is a secreted pore-forming toxin that induces a wide range of cellular responses. Like many other bacterial toxins, VacA has been hypothesized to utilize lipid rafts to gain entry into host cells. Here, we use Giant Plasma Membrane Vesicles (GPMVs) as a model system to understand the preferential partitioning of VacA into lipid rafts. We show that a wild-type toxin predominantly associates with the raft phase. Acid activation of VacA enhances binding of the toxin to GPMVs but is not required for raft partitioning. VacA mutant proteins with alterations at the amino-terminus (resulting in impaired membrane channel formation) and a non-oligomerizing VacA mutant protein retain the ability to preferentially associate with lipid rafts. Consistent with these results, the isolated VacA p55 domain was capable of binding to lipid rafts. We conclude that the affinity of VacA for rafts is independent of its capacity to oligomerize or form membrane channels.

8. Development of a rapid and visual nucleotide detection method towards an Chinese epidemic strain of Orientia tsutsugamushi based on recombinase polymerase amplification assay and lateral flow test

This randomized clinical trial compares the effect of immediate antiretroviral therapy (ART) vs referral to the nearest health facility on linkage to care and viral suppression among ART-native adults in rural Lesotho who home-tested positive for HIV.

Recent estimates indicate that approximately 57% of the 36.7 million people living with HIV worldwide are in care and receiving antiretroviral treatment (ART). Although this represents a 20-fold increase in less than 2 decades in the number of people receiving ART, these findings also demonstrate that the global community is still far from achieving the targets laid out by the Joint United Nations Programme on HIV/AIDS (UNAIDS) called 90-90-90—specifically, 90% of all people living with HIV knowing their status; 90% of those diagnosed receiving sustained ART; and 90% of those receiving ART achieving viral suppression by 2020. Accomplishing this ambitious agenda requires sustainable approaches in countries with the highest burden of HIV.

13. High Medication Possession Ratios Associated with Greater Risk of Virologic Failure Among Youth Compared to Adults in a Nigerian Cohort

AbstractBackground:Medication possession ratio (MPR) is widely used as a measure of adherence to antiretroviral therapy (ART). Many adolescents and young adults (AYA) experience ART adherence challenges. Our objective was to determine whether the relationship between MPR and virologic failure (VF) is consistent between AYA and older adults in Nigeria.Methods:We conducted a retrospective study of AYA (15-25 years) and adults (>25 years) who initiated ART between January 2009 and December 2012 at 10 university-affiliated HIV clinics in Nigeria. We used multivariate generalized linear models to assess the relationship between age, MPR (ART doses dispensed)/(days since ART initiation), and risk of VF (HIV RNA >1,000 copies/mL) in the first year on ART.Results:The cohort included 1,508 AYA and 11,376 older adults. VF was more common in AYA than older adults (30% vs. 24% p94%, 80-94%, and 94% aRR 0.43, p1,000 copies/mL) in the first year on ART.
Results:
The cohort included 1,508 AYA and 11,376 older adults. VF was more common in AYA than older adults (30% vs. 24% p94%, 80-94%, and 94% aRR 0.43, p

AbstractBackground:HIV-1 CRF01_AE is dominant in Thailand where RV144 vaccine trial was conducted. To study immune correlates of protection in ongoing trials, CRF01_AE derived reagents are essential. Here we present a panel of 14 HIV-1 infectious molecular clones (IMC) identified from different stages of infection, and characterization of their neutralization sensitivity using two standard assays.Methods:One full-length IMC was constructed using a transmitted-founder virus to express Renilla luciferase (LucR) reporter gene and full-length envelopes (envs) of exogenous HIV-1. A panel of IMCs was generated, expressing envs of viruses from acute (Fiebig stages I/II and I-IV) and chronic (>Febig VI) infection. Neutralization assays were performed using TZM-bl or A3R5 cell lines, and sera or monoclonal antibodies (mAbs). Wilcoxon matched-paired test was used to assess neutralization differences between assays and reagents; correlation coefficients were evaluated by linear regression.Results:Neutralization potency observed was significantly higher in the A3R5 assay when testing mAbs and serum pools (p

17. Phenotyping Cardiac Arrest: Bench and Bedside Characterization of Brain and Heart Injury Based on Etiology

18. Plasmodium Gametocytes in Field Studies: Do We Measure Commitment to Transmission or Detectability?

Trends in Parasitology, 12.03.2018Tilføjet 13.03.2018 09:25

Cristian Koepfli, Guiyun Yan

The proportion of Plasmodium spp. infections carrying gametocytes, and gametocyte densities, are often reported as surrogate markers for transmission potential. It remains unclear whether parasites under natural conditions adjust commitment to transmission depending on external factors. Population-based surveys comprising mostly asymptomatic low-density infections are always impacted by the sensitivity of the assays used to diagnose infections and detect gametocytes. Asexual parasite density is an important predictor for the probability of detecting gametocytes, and in many cases it can explain patterns in gametocyte carriage without the need for an adjustment of the gametocyte conversion rate.

19. Potential role for regulatory B cells as a major source of IL-10 in spleen from Plasmodium chabaudi-infected mice [PublishAheadOfPrint]

IL-10-producing regulatory B (Breg) cells were found to be induced in a variety of infectious diseases. However, its importance in the regulation of immune response to malaria is still unclear. Here, we investigated the dynamic, phenotype and function of Breg cells using the Plasmodium chabaudi chabaudi AS (P.c. chabaudi AS) infected C57BL/6 and BALB/c mice. BALB/c mice were more susceptible to infection and had a stronger IL-10 response in spleen compared with C57BL/6 mice. Analysis of the surface markers of IL-10-producing cells with flow cytometry showed that CD19+ B cells were one of the primary IL-10-producing populations in P.c. chabaudi AS infected C57BL/6 and BALB/c mice, especially in the later one. The Breg cells had heterogeneous phenotype which shifted during infection. The well-established Breg subset, CD19+CD5+CD1dhi cells, accounted for less than 20% of IL-10-producing B cells in both strains during the course of infection. Most Breg cells were IgG+ and CD138- from day 0 to day 8 post infection. Adoptive transfer of Breg cells to C57BL/6 mice infected with P.c. chabadui AS led to transient increase of parasitaemia without impact on survival rate. Our finding reveals that B cells play an active and important regulatory role in addition to mediating humoral immunity in immune response against malaria, which should be paid more attention in developing therapeutic or vaccine strategy against malaria involving stimulation of B cells.

20. Quantifying the aftermath: Recent Outbreaks among People who in- ject Drugs and the Utility of Phylodynamics

We showed that human IgG supported the response by human innate immune cells to peptidoglycan (PGN) from Bacillus anthracis and PGN-induced complement activation. However, other serum constituents have been shown to interact with peptidoglycan, including the IgG-like soluble pattern recognition receptor serum amyloid P (SAP). Here, we compared the ability of SAP and of IgG to support monocyte and complement responses to PGN. Utilizing in vitro methods, we demonstrate that SAP is superior to IgG in supporting monocyte production of cytokines in response PGN. Like IgG, the response supported by SAP was enhanced by phagocytosis and signaling kinases such as Syk, Src and phosphatidylinositol 3-kinase that are involved various cellular processes including Fc receptor signaling. Unlike IgG, SAP had no effect on the activation of complement in response to PGN. These data demonstrate an opsonophagocytic role for SAP in response to PGN that propagates a cellular response without propagating the formation of the terminal complement complex.

24. Signaling by a conserved quorum sensing pathway contributes to growth ex vivo and oropharyngeal colonization of human pathogen group A streptococcus [PublishAheadOfPrint]

Bacterial virulence factor production is a highly coordinated process. The temporal pattern of bacterial gene expression varies in different host anatomic sites to overcome niche-specific challenges. The human pathogen group A streptococcus (GAS) produces a potent secreted protease, SpeB, that is crucial for pathogenesis. Recently, we discovered that a quorum-sensing pathway comprised of a leaderless short peptide, SpeB-inducing peptide (SIP), and cytosolic global regulator, RopB, controls speB expression in concert with bacterial population density. The SIP signaling pathway is active in vivo and contributes significantly to GAS invasive infections. In the current study, we investigated the role of the SIP signaling pathway in GAS-host interactions during oropharyngeal colonization. The SIP signaling pathway is functional during growth ex vivo in human saliva. SIP-mediated speB expression plays a crucial role in GAS colonization of the mouse oropharynx. GAS employs a distinct pattern of SpeB production during growth ex vivo in saliva that includes a transient burst of speB expression during early stages of growth coupled with sustained levels of secreted SpeB protein. SpeB production aids GAS survival by degrading LL37, an abundant human antimicrobial peptide. We find that SIP signaling occurs during growth in human blood ex vivo. Moreover, the SIP signaling pathway is critical for GAS survival in blood. SIP-dependent speB regulation is functional in strains of diverse emm types, indicating that SIP signaling is a conserved virulence regulatory mechanism. Our discoveries have implications for future translational studies.

Ethanolamine is a ubiquitous and essential molecule within a host. Significantly, bacterial pathogens exploit ethanolamine during infection to promote growth and regulate virulence. The ethanolamine permease EutH is dispensable for growth in vitro under standard conditions, whereas EutH is required for ethanolamine utilization at low pH. These findings suggested a model in which EutH facilitates diffusion of ethanolamine into the bacterial cell in acidic environments. To date, the ecological significance of this model has not been thoroughly investigated, and the importance of EutH to bacterial growth under physiologically relevant conditions is not known. During infection, immune cells internalize invading bacteria within an acidic, nutrient deplete vacuole, called the phagosome. Here, we investigated the hypothesis that EutH promotes bacterial survival following phagocytosis. Our findings indicate that EutH is important for survival and replication of the facultative intracellular pathogens Salmonella enterica serovar Typhimurium and Listeria monocytogenes during prolonged or transient exposure to the phagosome, respectively. Furthermore, in agreement with EutH being important in the acidic environment, neutralization of the vacuole abolished the requirement for EutH. Significantly, consistent with a role for EutH in promoting intramacrophage survival, EutH was not required during S. Typhimurium local intestinal infection but specifically conferred an advantage upon dissemination to peripheral organs. These findings reveal a physiologically relevant and conserved role for EutH in spatiotemporal niche adaptation during infection.

27. The Impact of Hla Allele-Kir Pairs on Disease Outcome in Hiv-Infected Thai Population

Prevention of tick-borne diseases in humans is challenging. To date, no prevention strategies have been shown to be consistently effective. Here, we describe the design of a new large-scale study, involving hundreds of households in Dutchess County, New York, testing whether environmental interventions, applied intensively and over 4 years, can prevent human cases.

Phytoplasmas are plant pathogenic bacteria transmitted by hemipteran insects. The leafhopper Euscelidius variegatus is a natural vector of chrysanthemum yellows phytoplasma (CYp) and a laboratory vector of Flavescence dorée phytoplasma (FDp). The two phytoplasmas induce different effects on this species: CYp slightly improves, while FDp negatively affects insect fitness. To investigate the molecular bases of these different responses, RNA-seq analysis of E. variegatus infected with either CYp or FDp was performed. The sequencing provided the first de novo transcriptome assembly for a phytoplasma vector, and a starting point for further analyses on differentially regulated genes, mainly related to immune system and energy metabolism. Insect phenoloxidase activity, immunocompetence, and body pigmentation were measured to investigate the immune response, while respiration and movement rates were quantified to confirm the effects on energy metabolism. The activation of insect immune response upon FDp infection, which is not naturally transmitted by E. variegatus, confirmed that this bacterium is mostly perceived as a potential pathogen. Conversely, the acquisition of CYp, which is naturally transmitted by E. variegatus, seems to increase the insect fitness by inducing a prompt response to stress. This long-term relationship is likely to improve survival and dispersal of the infected insect, thus enhancing the opportunity of phytoplasma transmission.

Left ventricular assist systems are increasingly used in patients with advanced heart failure, and concerns about device durability due to pump thrombosis have emerged. An intrathoracic, fully magnetically levitated centrifugal-flow pump that was designed to prevent pump thrombosis has been…

A 21% increase in US birth defects most strongly associated with gestational Zika virus infection (ZVI) was observed in regions of local transmission at the end of 2016, according to a recent CDC report. Infection with the virus during pregnancy has been strongly linked to microcephaly and other brain abnormalities, eye deformities, and other types of central nervous system dysfunction.